Angiotensin II is an active center of the renin-angiotensin system, and has powerful vasopressor action and stimulating action for the synthesis and secretion of aldosterone in the adrenal cortex. It is also known to be a substance causing hypertension. Its action is considered to be caused through a specific receptor on various target organs such as adrenal cortex, kidneys, arterioles and the peripheries of sympathetic nerves.
Known conventional examples of substances which show antihypertensive effects by pharmacological inhibition of the renin-angiotensin system include angiotensin-converting enzyme inhibitors such as captopril and enarapril, angiotensin II antagonists and renin inhibitors. As angiotensin II antagonist out of these, saralasin ([Sar1, Ala8] AGII), which is an angiotensin II type peptide, and nonpeptide derivatives such as imidazole derivatives (Japanese Patent Laid-Open Nos. SHO 56-7103 and SHO56-71074, and Japanese Language Laid-Open Publication No. HEI 3-501020) and pyrazole derivatives (Japanese Patent Laid-Open No. HEI 3-218371) are already known.
The peptide derivatives, however, have difficulty in clinical applications because of their short in vivo half-life, lack of effectiveness upon oral administration and significant agonistic activities. Among the nonpeptide derivatives, few drugs have been used clinically.
With a view toward providing a clinically excellent drug under such circumstances, the present inventors have carried out an extensive investigation. As a result, finding that an N-biphenylmethylthiadiazoline derivative represented by the below-described formula (7) or salt thereof has an excellent angiotensin II antagonistic action and are useful as therapeutics for circulatory diseases such as hypertension, heart diseases and cerebral apoplexy, the present inventors have already filed international patent application thereon (WO94/04516).
In that international application, an N-biphenylmethylthiadiazoline derivative (7) is prepared in accordance with the process as shown by the following reaction scheme.
wherein R.sup.1 represents a lower alkyl group.
The above process is however accompanied with the drawback that it includes a step of introducing a tetrazole group into a biphenylnitrile derivative in a manner known to date (Japanese Patent Laid-Open No. SHO 63-23868) so that a harmful trialkyltin compound should be used as a reagent for tetrazole introduction. The above process is therefore not fully satisfactory from the industrial viewpoint.
An object of the present invention is therefore to provide an industrially useful process for producing an N-biphenylmethylthiadiazoline derivative (7) or salt thereof which is an angiotensin antagonist, and also an intermediate for producing the same.